Faculty Peer Reviewed
Helminths–parasitic worms that have co-evolved with humans and colonized our gastrointestinal (GI) tract for millennia–have developed the ability to modulate our inflammatory responses and evade our immune systems to survive [1,2]. Until the 1930s, the helminth colonization of humans was almost universal, owing to poor sanitation conditions and an impure food supply [3,4]. This changed as the economic development of the last century created improved sanitary conditions: clean running water, hygienic farming practices, and better medical services, ultimately eradicating helminth infections in the modern world .
But has improved sanitation come at a cost?
With the eradication of helminth infections, statistics have shown a concomitant increase in the incidence of inflammatory bowel disease, including Crohn’s disease (CD) and ulcerative colitis (UC), both chronic immune diseases of the GI tract . Prior to 1940, inflammatory bowel disease (IBD) was almost non-existent worldwide. Today IBD affects more than three million people in the United States and Europe. Conversely, in developing countries with high rates of helminth colonization, the incidence of IBD remains much lower . The increase in IBD with the improved sanitation and cleanliness of modern society has been dubbed the hygiene hypothesis.
The IBD hygiene hypothesis states that “raising children in extremely hygienic environments negatively affects immune development” . This is because over thousands of years our immune systems and intestinal linings have adapted to co-evolution with infectious agents like helminths. Non-exposure can lead to altered immune system development, predisposing humans to immunologic diseases like IBD [5, 11]. This hypothesis is supported by the geographical gradient in the incidence of IBD: while the US and northern Europe have high incidence rates, countries in South America, Asia, and Africa have minuscule incidence rates. However, the gap in IBD incidence rates is beginning to narrow as developing countries adopt modern hygienic practices and their exposure to infectious agents like helminths decreases . Studies have also shown an incidence rate stratification among climates, with tropical locales seeing increased rates of infection and less cases of IBD, and temperate regions showing the inverse [3,4]. This hypothesis is further supported by epidemiological studies that have found an increased risk of IBD in the offspring of migrants who relocate from developing to developed countries compared to peers in their country of origin .
IBD is thought to be caused by an uncontrolled immune response to normal gut flora, leading to an imbalance in the response of T-helper cells . Genetic susceptibility in addition to an increased ratio of Th1/Th2 cell lines is hypothesized to cause IBD. The Th1 immune response is responsible for cell-mediated actions needed for viral infections and intracellular pathogens, while the Th2 response is activated to initiate an antibody response against foreign invaders like helminths. Th1 cells release inflammatory cytokines such as interferon-gamma and tumor necrosis factor-alpha, causing subsequent mucosal inflammation of the GI tract, while Th2 cells release the anti-inflammatory cytokine interleukin-10 (IL-10). The Th1 and Th2 cell lines cross-regulate one another through their respective cytokines. The decrease in helminth exposure has led to a decrease in activation of Th2 cell response, leading to an unchecked, inappropriate Th1 predominance in the immune systems of patients living with IBD [7,8].
The imbalance in Th2 and Th1 cell response is the basis for the use of helminths as therapy for IBD. The belief is that if patients are exposed to helminths, the immune system will respond with an increase in Th2 cell activation and production. This response will then lead to a release of host compounds that trigger the release of an anti-inflammatory cytokine such as IL-10, in addition to down-regulating the pro-inflammatory Th1 response [7,8].
So does helminth therapy actually work?
Researchers began the study of helminth therapy using murine models. Colitis was induced in mice using various chemical challenges and the mice were subsequently infected with various helminths. These studies showed that helminth infections could both prevent and alleviate colitis in animals [5,8]. Following the success in murine models, scientists performed clinical studies with the porcine whipworm, Trichuris suis, in patients with both CD and UC. T. suis was chosen as a good candidate for use in humans because the larvae and adults cannot leave the intestines or multiply within humans, and transmission from person to person is inhibited by normal hygienic practices [4,6].
The first human study was an open-label trial treating 7 combined UC and CD patients with a one-time dose of 2500 microscopic T. suis ova . Both subsets of patients showed clinical improvement with no adverse side effects. A second study treated 29 CD patients with 2500 ova every 3 weeks for 24 weeks. 23 of 29 (79%) responded positively, with 21 going into complete remission . Following this success, a double-blind, placebo-controlled, randomized clinical trial assessed the efficacy and safety of T. suis ova therapy in 54 patients with UC. The results found an improvement in 43.3% of patients treated with the regimen of 2500 T. suis ova orally every 2 weeks for 12 weeks, and only a 16.7% improvement rate in the placebo group. The patients experienced no side effects and the researchers concluded that “ova therapy seems safe and effective in patients with active colitis” .
Helminth therapy research is in its infancy, and, as with all new therapies, caution should be taken to prevent potentially harmful effects of treatment. A major obstacle is the availability of safe sources of clinical-grade material for use in clinical trials. While some helminths are known to cause serious side effects, including liver fibrosis and portal hypertension, the worms that have been studied thus far have been carefully selected to cause relatively minor side effects . Currently, IBD has no cure beyond surgery (for ulcerative colitis), and the main treatments are immunosuppressive medications like glucocorticoids, anti-metabolites, and biologics that can increase susceptibility to serious infections . The IBD patient population is in need of new treatments, and helminth-derived therapy might be the next breakthrough in the control of these diseases. While studying the potential benefits of helminth exposure is a start, the ultimate goal for helminthic treatment may not lie in actually infecting patients with the worms, but instead discovering immunomodulatory molecules that allow helminths to effectively modulate the human immune system . Research on this topic is already underway, and the filarial nematode-derived immunomodulatory molecule ES-62 is one potential therapeutic agent being actively pursued . Some preliminary studies indicate that helminth extracts are as effective as treatment with live helminths, and would provide a much less offensive treatment than live worms .
Perhaps reuniting with the creatures that have been eliminated from the modern hygienic environment will become a legitimate source of effective treatment for those with IBD. As Joel Weinstock, one of the leading researchers in the study of helminthic therapy, said in an interview with the New York Times, ”We’re part of our environment; we’re not separate from it.” Adopting this theory and embracing our surroundings in therapeutic research might be the breakthrough IBD patients have been awaiting .
Michael Guss is a 4th year medical student at NYU Langone Medical Center
Peer reviewed by P’ng Loke, MD, Medical Parasitology, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
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